1. Technical Field
This invention relates to stabilization against auto radiolysis of a glucose compound that incorporates an 18F radioisotope. The stabilized compound is used for diagnostic imaging using Positron Emission Tomography (PET). Related inventions may be found in U.S. main class 424, subclass 1.89.
2. Background
The 18F isotope-labeled glucose, [18F] 2-Fluoro-2-Deoxy-D-glucose (hereinafter FDG), has become widely used in nuclear medicine for diagnostic studies using a Positron Emission Tomography (PET) body scanning technique. Because of the short half-life of the 18F isotope (109 min), this product must be produced in relatively large quantities to allow for decay during delivery to the patient from a manufacturing facility. Therefore, work shifts usually start near midnight with production for distant (via automobile) hospitals first, followed by that for nearby hospitals in the very early morning. Typical delivery time can be as long as 5–8 hours. After arrival, there could be another 4 hour delay before use on the last patient. Thus, 8–12 hours can pass from the time of production to the time of administration to a patient. This is 4.4–6.6 half-lives and necessitates preparation of initial radioactivity concentrations of 20–100 times greater than is actually required at the time of administration.
(Although not the only method, currently, the preferred method of producing the 18F isotope is by bombarding water enriched with the 18O isotope using high energy protons from a cyclotron. Additional information may be found in U.S. Pat. No. 6,567,492, issued May 20, 2003 to Kiselev et al., and the references cited therein.)
If prepared in relatively high concentrations, for example, 3.7 GBq/ml (100 mCi/ml) and higher, radiation-induced decomposition of FDG is observed. This process is referred to as radiolysis. It is caused mainly by oxidation by free radicals that are produced by the interaction of ionizing radiation from the 18F isotope with the water solvent and possibly air. These processes may then lead to the decomposition of FDG, which can be quantified in terms of decreased Radio Chemical Purity (RCP). RCP is typically expressed as a % of activity in the form of FDG relative to the total radioactivity present in the sample.
At the end of production, FDG typically has an RCP of 98–100%. As a result of radiolysis, some FDG molecules decompose resulting in other than FDG radioactive substances (mainly free 18F− ions). As demonstrated by experiments described below, this can lead to a decline in RCP to less than 90% over a period of less than 12 hours. The quality standard established by the US Pharmacopoeia (USP) for FDG is “not less than 90% RCP.” It is obviously desirable to retain as high an RCP as possible for as long as possible to achieve the best PET image quality.
FDG production comprises synthesis of the 18F labeled compound followed by purification. Synthesis involves an 18F fluorination step which leads to formation of an acetylated derivative of FDG (an intermediate product) and then a hydrolysis step during which protective acetyl groups are removed resulting in the final product. The hydrolysis step takes only about 10 minutes, but the concentration of radioactive material is about five times as high as in the final product leading to significant decomposition of the FDG intermediate as it is being produced. Decomposition of the intermediate product will not directly affect the RCP of the final product due to the fact that accumulated radioactive impurities are removed during the purification step. However, it is important to realize that any decomposition will result in a lower radiochemical yield. Therefore, it is very useful to reduce or control radiolysis not only of the final product but also the intermediate product during hydrolysis.
For the purpose of distribution and use, the 12 hour storage capability is a practical requirement. Therefore, RCP after 12 hours or longer is a useful indicator of stabilization effectiveness.
In summary, improving the stability of FDG and increasing the RCP at the time of administration is an important goal for FDG manufacturers. It is also important to control radiolysis during the FDG production steps to increase radiochemical yield of the product.
Production of 18F-labeled FDG is, by now, well, known. Information can be found in: 1) Fowler et al., 2-Deoxy-2-[18F]Fluoro-D-Glucose for Metabolic Studies: Current Status,” Applied Radiation and Isotopes, vol. 37, no. 8, 1986, pages 663–668; 2) Hamacher et al., “Efficient Stereospecific Synthesis of No-Carrier-Added 2-[18F]-Fluoro-2-Deoxy-D-Glucose Using Aminopolyether Supported Nucleophilic Substitution,” Journal of Nuclear Medicine, vol. 27, 1986, pages 235–238; 3) Coenen et al., “Recommendation for Practical Production of [2-18F]Fluoro-2-Deoxy-D-Glucose,” Applied Radiation and Isotopes, vol. 38, no. 8, 1987, pages 605–610 (a good review); 4) Knust et al., “Synthesis of 18F-2-deoxy-2-fluoro-d-glucose and 18F-3-deoxy-3-fluoro-D-glucose with no-carrier-added 18F-fluoride,” Journal of Radioanalytic Nuclear Chemistry, vol. 132, no. 1, 1989, pages 85+; 5) Hamacher et al., “Computer-aided Synthesis (CAS) of No-carrier-added 2-[18F]Fluoro-2-Deoxy-D-Glucose: An Efficient Automated System for the Aminopolyether-supported Nucleophilic Fluorination,” Applied Radiation and Isotopes, vol. 41, no. 1, 1990, pages 49–55; and 6) U.S. Pat. No. 5,932,178, issued Aug. 3, 1999 to Yamazaki et al. for “FDG Synthesizer Using Columns.”
With respect to stabilization of radiopharmaceuticals, U.S. Pat. No. 5,762,907, issued Jun. 9, 1998 to Simon et al., discloses a freeze/thaw technique to preserve the radiopharmaceutical, ethylenediamine-tetraehtylenephosphonic acid (EDTMP), labelled with, for example, 153Sm. Radiometric degradation versus time is compared to solutions containing 0.9% benzyl alcohol, 5.0% ethanol, and a no-preservation control. The benzyl alcohol solution delays the start of degradation, after which the rate is moderate. In contrast, even at the high 5.0% concentration, ethanol delays degradation slightly, but then degradation proceeds at an even faster rate than the control. Use of other additives to stabilize various radiopharmaceuticals was discussed in U.S. Pat. No. 5,384,113, issued Jan. 24, 1995 to Deutsch et al.; U.S. Pat. No. 6,027,710, issued Feb. 11, 2000 to Higashi et al.; U.S. Pat. No. 6,066,309, issued May 23, 2000 to Zamara et al.; and U.S. Pat. No. 6,261,536, issued Jul. 17, 2001 to Zamara et al.
Mention can be made of US pre-grant publication 2002/0127181, dated Sep. 12, 2003 and applied for by Edwards et al. This application discusses a very wide range of radiopharmaceuticals useful in producing angiograms. Paragraphs 0238 and 0239 discuss synthesis of FDG labeled with 18-F. The next paragraph lists a number of stabilizers “comprising an effective amount of one or more stabilizers selected from ascorbic acid, benzyl alcohol, gentisic acid or its metal salts, p-aminobenzoic acid or its salt forms, cysteamine, 5-amino-2-hydroxybenzoic acid or its metal salt forms, nicotinic acid or its metal salt, nicotinamide, polyhydroxylated aromatic compounds, aromatic amines, and hydroxylated aromatic amines.” But no mention is made of ethanol. Paragraph 0266 lists additional stabilizers as cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, and inositol, again without mentioning ethanol. However, the next paragraph states that “Solubilization aids useful in the preparation of radiopharmaceuticals . . . include but are not limited to ethanol (emphasis added), glycerin . . . . Preferred solubilization aids are polyethylene glycol and Pluronics.”
Since the PET procedure requires injecting the FDG solution, there is a USP requirement to keep any ingredient with toxic potential within appropriate limits. Currently, the allowed dose of the above cited ethanol in the European Pharmacopoeia and USP is 0.5% (one tenth the concentration used above for EDTMP). Moreover, conformance requires demonstration by one or more validated limit tests. From a practical standpoint, it is very desirable to keep the concentration of any such potentially toxic ingredients at or below one half of the limit value, i.e., 0.25%. Because of assay uncertainty and safety factor considerations, using more than about one half the limit value requires considerably more testing to demonstrate conformance with confidence.